The long-term objective of this proposal is to design and develop potent and highly specific inhibitors of the enzyme aldose reductase. Aldose reductase catalyzes the reduction of glucose to sorbitol. It has been implicated in the pathogenesis of the chronic complications of diabetes mellitus. Current inhibitors of this enzyme lack specificity and potency, and are associated with undesirable side effects. BioCryst's experience with the structure-based design of inhibitors of purine nucleoside phosphorylase indicates that knowledge of the three-dimensional structure of a target enzyme, and its active site, is a tremendous aid to the development of inhibitors that are both safe and highly specific. BioCryst has solved and refined the X-ray crystal structure of porcine aldose reductase apo-enzyme, and has obtained crystals and solved the structures of both porcine and human aldose reductase complexed with its cofactor NADPH. Our goal is to locate and characterize the binding sites of the enzymatic substrate glucose and the best existing aldose reductase inhibitors (Phase I), and then design and synthesize potent and specific inhibitors of the enzyme based on this information (Phase II).